Throughout this application various publications are referenced, many in parenthesis. Full citations for each of these publications are provided at the end of the Detailed Description. The disclosures of each of these publications in their entireties are hereby incorporated by reference in this application.
Abnormal proliferative or hyperproliferative conditions include hypoproliferative disorders such as cancer, tumors and hyperplasias, including smooth muscle cell proliferation in the blood vessels (such as stenosis or restenosis following angiopathy). In these conditions, a means to control or inhibit (decrease) hyperproliferation is desirable. Many types of cellular mechanisms/molecules have been or could be associated with regulation of cellular proliferation. For example, the reversible phosphorylation of proteins on serine and threonine residues is a major intracellular control mechanism that regulates cell proliferation. The phosphorylation state of a protein is controlled by kinases, which phosphorylate proteins, and phosphatases, which dephosphorylate proteins. A number of families and types of protein phosphatases exist, including tyrosine phosphatases and serine/threonine protein phosphatases (PPs). An increase in expression of certain PPs has been described in several tumor types. Therefore, one could speculate that inhibitors of PP expression may have an effect on tumors (such as an anti-proliferative effect).
Small molecule inhibitors of protein phosphatases have been used to study PP function. The best characterized of these is okadaic acid, which is the causative agent of diarrhetic shellfish poisoning. It is a potent inhibitor of PP2A and PP1 and a much (roughly a thousandfold) less potent inhibitor of PP2B. Other inhibitors of one or more PPs include tautomycin, cyclosporin A, dinophysistoxin, calyculin, microcystin, nodularin and cantharidin (Cairns et al. 1994; Wera and Hemmings 1995).
One could also speculate that antisense oligonucleotides could be used to inhibit PP expression. Antisense oligonucleotides have been safely administered to humans and clinical trials of several antisense oligonucleotide drugs, targeted both to viral and cellular gene products, are presently underway.
In addition to the role of PPs in cell proliferation, glucocorticoids are another example of a cellular molecule which has been associated with cellular proliferation. Glucocorticoids are known to induce growth arrest in the G1-phase of the cell cycle in a variety of cells, both in vivo or in vitro, and have been shown to be useful in the treatment of certain cancers. The glucocorticoid receptor (GR) belongs to an important class of transcription factors that alter the expression of target genes in response to a specific hormone signal. Accumulated evidence indicates that receptor associated proteins play key roles in regulating glucocorticoid signaling. The list of cellular proteins that can bind and co-purify with the GR is constantly expanding. PP5 has been shown to be one of the proteins that co-immunoprecipitated with GR (Chen et al, 1996).
These two, PP5 and glucocorticoids, are merely two examples of many cellular mechanisms/molecules which have been associated with regulation of cellular proliferation. A need continues to exist to elucidate further means to regulate cell proliferation, in particular to decrease cell proliferation in hyperproliferative disorders.
Glucocorticoids are also used for their anti-inflammatory effect on the skin, joints, and tendons. They are important for treatment of disorders where inflammation is thought to be caused by immune system activity, such as rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, and connective tissue diseases like systemic lupus erythmatosus. They are used to treat asthma and are widely used with other drugs to prevent the rejection of organ transplants. Some cancers of the blood (leukemias) and lymphatic system (lymphomas) may also respond to corticosteroid drugs. A method of enhancing the beneficial effects of glucocorticoid therapy in these instances would always be desirable.